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AICR Spotlight Research: Meet Daniel W. Rosenberg, PhD

Uncovering How Your Gut Bacteria May Influence Colon Cancer Risk

Researchers now know that the trillions of microbes teeming in your gut are essential for good health and may play a role in cancer prevention. Bacteria and other microbes help to break down plant-based compounds, converting them into other metabolites well-studied for their anti-cancer activity. It’s possible that your specific set of microbes and your diet interact to influence cancer risk in very unique ways that may differ from those of your neighbors, says AICR grantee Daniel W. Rosenberg, PhD, director of the Colon Cancer Prevention Program at the University of Connecticut Health Center.

Dr. Rosenberg, who presented at the AICR Research Conference in November, focuses much of his research on understanding how our gut microbes’ metabolism of the plant compound ellagic acid—found in walnuts and other plant foods—influence inflammation and colorectal cancer risk. With his current AICR grant, he is testing if walnut consumption produces differing anti-inflammatory effects depending upon the person’s gut microbiome, the collection of all the bacteria and other microbes present in the gut. This relatively small clinical trial has recently led to a major research grant by the National Institutes of Health.

The research has the potential to better understand and develop ways to promote specific gut microbes that increase the formation of cancer-protective metabolites. Here, Dr. Rosenberg shares how his interests in toxicology and diet and intriguing lab studies on cancer led to his current research.

Q: How did you get interested in studying colorectal cancer prevention and diet?

A: I was at the University of Michigan getting my PhD—I started in environmental science then moved to biochemistry and ended up at Michigan in toxicology. I spent the last three years in environmental science studying pharmacology; I started transforming into a cancer biologist. I began to focus on the environment and cancer and then ramped up looking at cancer and lifestyle.

For me, that was always the scariest thing that could happen from an environmental exposure—diet increasing the risk of cancer. The most important aspect of toxicology and environmental health to me was cancer and since I had been working on basic pharmacology in the intestine, it all started to connect. I always suspected that chemicals in our diet would have a huge impact in the colon and it turns out it does. Colorectal cancer is the second leading cause of cancer death in the United States for men and women combined and now it’s becoming even more troubling because there’s an increase in early onset colorectal cancer.

Q: Are you also studying this?

A: Yes, I’ve been interested in early onset colorectal cancer for years. It might be activated through the microbiome. We are seeing more and more cases of people in their 20s and 30s with colorectal cancer; something is clearly going on.

Q: What led you to your current research in diet and the microbiota?

A: I started getting interested in cancer prevention when I was at a meeting about 10 years ago about different natural products. I got interested in black raspberry and cancer prevention. We published some papers on black raspberries and ulcerative colitis that showed a pretty strong effect. We started looking at other natural dietary compounds and walnuts are a rich source of many. We didn’t even know about ellagitannins (one of which is ellagic acid) at this point and there were only a few papers about walnuts and cell cultures. We were always interested in omega 3 fatty acids, and started exploring walnuts as a source of omega 3. After we published the first paper on walnuts in a cancer model we saw some beneficial effects, but we found the walnuts had a protective effect on male mice but not female. We couldn’t make sense of what walnuts were doing in these mice; we couldn’t come up with an explanation.

It was around this time that The Jackson Laboratory opened their Genomic Medicine building at our institute, and George Weinstock and I started talking. He is at Jackson, and is one of the world’s most famous microbiologists and a leading figure studying the microbiome in humans and in mice. It turns out the walnut has a really interesting effect on the microbiome. We started to see if we could run a clinical study in people with walnuts.

Q: And this takes us to your AICR study. Can you describe it?

A: We designed a clinical study where healthy people—all over age 50—eat walnuts daily for three weeks. They are given a small handful (42 grams). We look at their stool, urine and blood samples, and then biopsy specimens collected during their colonoscopy.

We are measuring the levels of urolithin and its anti-inflammatory properties. Ellagitannin is a polyphenol that breaks down to release free ellagic acid that travels to the colon where it enters the microbiome and gets metabolized into a host of urolithin molecules. Most are understudied and the most understudied, urolithin A, is potent in preventing ulcerative colitis. It seems to have anti-inflammatory, anti-cancer properties.

But here’s the most amazing thing about this pathway: a group in Spain has been arguing that not everyone has the same capacity to make urolithin A from ellagic acid. We don’t think it’s that simple but from our first 40 patients I can tell you with certainty that three of these patients made zero; they have no ability to make urolithin A. About a dozen made low levels; and some made high amounts. One person made a lot of urolithin A. Certain strains of microbes are doing this.

Q: Your hypothesis is that these metabolites will reduce the inflammation that is linked to increased risk of colon cancer.

A: We have found that the more urolithin your microbiome produces the more you will be protected, not just from colon cancer but other cancers as well. The walnut has caused shifts with (microbe) species; whether those are long-term permanent shifts or short, we don’t know.

Q: And the data from the AICR grant helped you secure a large NIH grant, correct?

A: Absolutely. The goal of the NIH grant is to expand the data that we have from the AICR study and go beyond what we’ve done before. The call was to study pre- and probiotics; we consider walnuts to be a pre-biotic, a substance that can change your microbiome. The NIH grant goal is to figure out what microbes are responsible for this metabolic pathway, which people are missing them and which people have them. If we can figure out the people missing certain microbes then maybe we can put them back in. We are proposing to study 200 people who are at elevated risk for colon cancer.

Without AICR we would never have gotten the NCI clinical trial funded, never in a million years. The amount of data we’ve generated is instrumental. It’s so compelling.

Q: What do you see as the big questions related to the microbiota and cancer?

A: We’re just beginning to understand the whole microbiota and cancer connection. It could be an important driver and an important way to limit cancer. There could be many bacteria driving and blocking cancer. We know fiber gets metabolized to butyrate, which seem to have a lot of protection.

We can’t discount the role that microbiome may play in cancer. We are still studying omega 3 fatty acids and how they and other components of the walnut —like Alpha-linolenic acid and fiber and melatonin—may be impacting the microbiome to modify urolithin formation. We don’t know—yet. Every time we unravel another level of the onion we find nine more things before we can solve this. It’s pretty amazing.

Dr. Daniel Rosenberg spoke about the manipulation of the gut microbiome for cancer prevention at AICR’s Annual Research Conference in November. For more about research on how to lower colorectal cancer, visit AICR’s latest report findings.

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